The Nox enzymes represent a family of membrane enzymes (Nox1, Nox2, Nox3, Nox4, Nox5, Duox1 and Duox2) that catalyze NADPH-dependent generation of superoxide and/or hydrogen peroxide. While these enzymes have normal biological functions in signal transduction and host defense, they have also been implicated in the pathogenesis of a variety of diseases. Nox inhibitors have therapeutic uses and uses in biological assays. See Jaquet et al., 2009. Antioxid Redox Signal. 11(10):2535-52.
The core catalytic domain of NOX enzymes share similar structure, and their only known biochemical function is the generation of reactive oxygen species (ROS). The basic catalytic subunit of NOX contains a C-terminal dehydrogenase domain featuring a binding site for NADPH and bound flavin adenine nucleotide (FAD), as well as an N-terminal domain consisting of six trans-membrane helices that bind two heme groups. Upon activation, NADPH transfers its electron to the FAD, which in turn passes electrons sequentially to two hemes and ultimately to molecular oxygen on the opposite side of the membrane to produce superoxide (O2—) and/or hydrogen peroxide (H2O2), depending upon the isoform. Although NOX-isoforms catalyze the reduction of the molecular oxygen, they differ in their tissue distribution, their subunit requirement, domain structure, and mechanism by which they are activated. Depending upon the clinical condition, either isoform selective, or Nox/Duox pan-specific inhibitors are contemplated to be useful for therapeutic applications. Potential Nox inhibitors have been investigated, such as diphenylene iodonium (DPI), apocynin, Nox2 B-loop peptide, VAS2870, and pyrazolopyridines. However, no isoform- or class-selective Nox inhibitors have been approved in humans for treatment of diseases by the FDA. There exists a need to identify inhibitors for Nox enzymes.
Certain quinazoline derivatives were identified in references. Hayao et al., J Med Chem 1965, 8:6, 807-11 disclose quinazoline derivatives produce vasodilation. See also U.S. Pat. No. 3,919,425. International PCT App. No. WO 2000/034278 discloses triazolo derivatives as chemokine inhibitors. US Patent App. No. 2009/0163545 discloses compounds for altering the lifespan of a eukaryotic organism identified using a DeaD assay.